Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

JQ1 promotes invasion in a BET protein independent manner in prostate cancer

ABSTRACT: Recent findings have shown that inhibitors targeting BET (bromodomain and extraterminal domain) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports also have revealed that JQ1 can activate additional oncogenic pathways and may affect EMT (epithelial mesenchymal transition). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein independent manner. Multiple invasion pathways including EMT, BMP (bone morphogenetic protein) signaling, chemokine signaling and focal adhesion pathway were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of FOXA1, an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1, inactivated FOXA1 binding to its interacting repressors, TLE3, HDAC7 and NFIC, thus blocking FOXA1 repressive function and activating the invasion genes. Our finding indicates that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents could not be ignored during cancer treatment, especially in FOXA1 related cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139230 | GEO | 2022/10/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Long non-coding RNA MANCR is a target of BET bromodomain protein BRD4 and plays a critical role for cellular migration and invasion abilities of prostate cancer

Project description:Androgen receptor (AR)-negative castration-resistant prostate cancer (CRPC) is highly aggressive and resistant to current therapies. BET bromodomain protein BRD4 binds to super-enhancers (SEs) that drive high expression of oncogenes in many cancers. A BET inhibitor JQ1 has been found to suppress malignant phenotypes of prostate cancer cells, however, the target genes of JQ1 remains largely unknown. Here we show that SE-associated genes specific for AR-negative CRPC PC3 cells include the genes involved in migration and invasion and that JQ1 impairs migration and invasion of PC3 cells. We identified the long non-coding RNA MANCR, which is markedly down-regulated by JQ1 and found that BRD4 binds to the MANCR locus. MANCR knockdown led to a significant decrease in migration and invasion of PC3 cells. RNA sequencing analysis revealed that expression of the genes involved in migration and invasion is altered by MANCR knockdown. In summary, our data demonstrate that MANCR has a critical role for cellular migration and invasion abilities of PC3 cells.

2020-03-23 | GSE145081 | GEO

JQ1 promotes invasion in a BET protein independent manner in prostate cancer

Project description:JQ1 promotes invasion in a BET protein independent manner in prostate cancer

| PRJNA578853 | ENA

RNF185 control of COL3A1 expression limits prostate cancer migration and metastatic potential.

Project description:RNF185 is a RING finger domain-containing ubiquitin ligase implicated in ER-associated degradation. Prostate tumor patient data analysis revealed a negative correlation between RNF185 expression and prostate cancer progression and metastasis. Likewise, several prostate cancer cell lines exhibited greater migration and invasion capabilities in culture upon RNF185 depletion. Subcutaneous inoculation of mouse prostate cancer MPC3 cells stably expressing shRNA against RNF185 into mice resulted in larger tumors and more frequent lung metastases.RNA-sequencing and Ingenuity Pathway Analysis identified wound healing and cellular movement among the most significant pathways upregulated in RNF185-depleted, compared to control prostate cancer cells. Gene Set Enrichment Analyses performed in samples from patients harboring low RNF185 expression and in RNF185-depleted lines confirmed the deregulation of genes implicated in EMT. Among those, COL3A1 was identified as the primary mediator of RNF185’s ability to impact migration phenotypes. Correspondingly, enhanced migration and metastasis of RNF185 KD prostate cancer cells were attenuated upon co-inhibition of COL3A1. Our results identify RNF185 as a gatekeeper of prostate cancer metastasis, partly via its control of COL3A1 availability.

2024-08-09 | PXD045473 | Pride

Targeting the MLL complex in castration-resistant prostate cancer [ChIP-seq]

Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens MDV3100 (enzalutamide), durable responses are limited, presumably due to acquired resistance. Recently, JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of ASH2L genome-wide binding in prostate cancer cells after AR stimulation.

2015-03-02 | E-GEOD-60841 | biostudies-arrayexpress

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (ChIP-Seq)

Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of AR, BRD2, BRD3, BRD4, ERG, RNA Pol II and H3K27ac in prostate cancer cells with respect to BET inhibitors

2014-04-25 | E-GEOD-55062 | biostudies-arrayexpress

Effect of FOXA1 overexpression in prostate cancer

Project description:FOXA1 is a transcription factor which aids AR function in prostate. There is controversary over the effect of high FOXA1 level has on prostate cancer so we forced the overexpression in the LNCaP prostate cancer cell line. LNCaP prostate cancer cell line was transfected with GFP control plasmid or plasmid containing FOXA1 full length cDNA. The effect on gene expression was assessed by microarray.

2014-01-03 | E-GEOD-49153 | biostudies-arrayexpress

RB-N phosphorylation promotes BRD4-mediated CREB signaling hyperactivation and BET inhibitor resistance

Project description:The combination of CREB inhibitor and JQ1 could overcome the resistance to BET inhibitors in RB loss prostate cancer. Our study firstly showed that GNB1L-CREB pathway was activated after RB loss and considered as the potential target for the prostate cancer therapy

2022-08-30 | GSE191263 | GEO

RB-N phosphorylation promotes BRD4-mediated GPCR signaling hyperactivation and BET inhibitor resistance

Project description:The combination of CREB inhibitor and JQ1 could overcome the resistance to BET inhibitors in RB loss prostate cancer. Our study firstly showed that ADRB2-CREB pathway was activated after RB loss and considered as the potential target for the prostate cancer therapy

2021-12-31 | GSE162897 | GEO

TMPRSS2 Influences Prostate Cancer Metastasis

Project description:TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastasis. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-Met receptor tyrosine kinase signaling, and initiated a pro-invasive EMT phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. Custom mouse cDNA microarrays were used to measure transcript levels in microdissected anterior prostate tumors from Tmprss2+/+;TRAMP mice, Tmprss2-/-;TRAMP mice or strain-matched benign epithelium. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.

2014-09-09 | E-GEOD-58822 | biostudies-arrayexpress

Determining the impact of the Bromodomain and extra-terminal inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer

Project description:To determine the impact of the Bromodomain and extra-terminal (BET) inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer we performed GATA2 ChIP-seq in the presence and absence of JQ1 and assessed differential binding upon JQ1 treatment for 24 hours. We first determined the GATA2 cistrome using our GATA2 ChIP-seq data. Overlapping this with previously published ChIP-seq data for the BET family of proteins (Asangani et al., 2014), we identified a substantial proportion of GATA2 genomic binding sites which are co-occupied by a BET protein. We then quantified differential binding of GATA2 upon JQ1 treatment genome-wide.

2019-01-17 | GSE125236 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data